tbuckley/cabot-search huggingface dataset:
Integrated multi-omics approach to distinct molecular characterization and classification of early-onset colorectal cancer
Authors: Mulong Du, Dongying Gu, Junyi Xin, Ulrike Peters, Mingyang Song, Guoshuai Cai, Shuwei Li, Shuai Ben, Yixuan Meng, Haiyan Chu, Lianmin Chen, Qianghu Wang, Lingjun Zhu, Zan Fu, Zhengdong Zhang, Meilin Wang
Journal: Cell Reports Medicine (2023)

Incidence of early-onset colorectal cancer (EOCRC), defined by a diagnosed age under 50 years, is increasing, but its heterogeneous etiologies that differ from general CRC remain undetermined. We initially characterize the genome, epigenome, transcriptome, and proteome of tumors from 79 patients in a Chinese CRC cohort. Data for an additional 126 EOCRC subjects are obtained from the International Cancer Genome Consortium Chinese cohort and The Cancer Genome Atlas European cohort. We observe that early-onset tumors have a high tumor mutation burden; increased DNA repair features by mutational signature 3 and multi-layer pathway enrichments; strong perturbations at effects of DNA methylation and somatic copy-number alteration on gene expression; and upregulated immune infiltration as hot tumors underlying immunophenotypes. Notably, LMTK3 exhibits ancestral mutation disparity, potentially being a functional modulator and biomarker that drives molecular alterations in EOCRC development and immunotherapies. This integrative omics study provides valuable knowledge for precision oncology of CRC.
Multiplex imaging of breast cancer lymph node metastases identifies prognostic single-cell populations independent of clinical classifiers
Authors: Jana Raja Fischer, Hartland Warren Jackson, Natalie de Souza, Zsuzsanna Varga, Peter Schraml, Holger Moch, Bernd Bodenmiller
Journal: Cell Reports Medicine (2023)

Although breast cancer mortality is largely caused by metastasis, clinical decisions are based on analysis of the primary tumor and on lymph node involvement but not on the phenotype of disseminated cells. Here, we use multiplex imaging mass cytometry to compare single-cell phenotypes of primary breast tumors and matched lymph node metastases in 205 patients. We observe extensive phenotypic variability between primary and metastatic sites and that disseminated cell phenotypes frequently deviate from the clinical disease subtype. We identify single-cell phenotypes and spatial organizations of disseminated tumor cells that are associated with patient survival and a weaker survival association for high-risk phenotypes in the primary tumor. We show that p53 and GATA3 in lymph node metastases provide prognostic information beyond clinical classifiers and can be measured with standard methods. Molecular characterization of disseminated tumor cells is an untapped source of clinically applicable prognostic information for breast cancer.
Society for Immunotherapy of Cancer (SITC) consensus definitions for resistance to combinations of immune checkpoint inhibitors with chemotherapy
Authors: Naiyer Rizvi, Foluso O Ademuyiwa, Z Alexander Cao, Helen X Chen, Robert L Ferris, Sarah B Goldberg, Matthew D Hellmann, Ranee Mehra, Ina Rhee, Jong Chul Park, Harriet Kluger, Hussein Tawbi, Ryan J Sullivan
Journal: Journal for ImmunoTherapy of Cancer (2023)

Although immunotherapy can offer profound clinical benefit for patients with a variety of difficult-to-treat cancers, many tumors either do not respond to upfront treatment with immune checkpoint inhibitors (ICIs) or progressive/recurrent disease occurs after an interval of initial control. Improved response rates have been demonstrated with the addition of ICIs to cytotoxic therapies, leading to approvals from the US Food and Drug Administration and regulatory agencies in other countries for ICI−chemotherapy combinations in a number of solid tumor indications, including breast, head and neck, gastric, and lung cancer. Designing trials for patients with tumors that do not respond or stop responding to treatment with immunotherapy combinations, however, is challenging without uniform definitions of resistance. Previously, the Society for Immunotherapy of Cancer (SITC) published consensus definitions for resistance to single-agent anti-programmed cell death protein 1 (PD-1). To provide guidance for clinical trial design and to support analyses of emerging molecular and cellular data surrounding mechanisms of resistance to ICI-based combinations, SITC convened a follow-up workshop in 2021 to develop consensus definitions for resistance to multiagent ICI combinations. This manuscript reports the consensus clinical definitions for combinations of ICIs and chemotherapies. Definitions for resistance to ICIs in combination with targeted therapies and with other ICIs will be published in companion volumes to this paper.
Response to: Correspondence on 'H3.3K27M mutation is not a suitable target for immunotherapy in HLA-A2+ patients with diffuse midline glioma' by Chheda<i>et al</i>
Authors: Lena Immisch, George Papafotiou, Oliver Popp, Philipp Mertins, Thomas Blankenstein, Gerald Willimsky
Journal: Journal for ImmunoTherapy of Cancer (2023)

Our discussion on the targetability of neoantigens in diffuse midline glioma (DMG) is important since (1) DMG as a pediatric high-grade glioma is a devastating disease and a major cause of childhood cancer deaths and (2) adoptive T cell therapy has been shown to be very efficient when targeting
CD47 expression is critical for CAR T-cell survival in vivo
Authors: Alex N Beckett, Peter Chockley, Shondra M Pruett-Miller, Phuong Nguyen, Peter Vogel, Heather Sheppard, Giedre Krenciute, Stephen Gottschalk, Christopher DeRenzo
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background CD47 is an attractive immunotherapeutic target because it is highly expressed on multiple solid tumors. However, CD47 is also expressed on T cells. Limited studies have evaluated CD47-chimeric antigen receptor (CAR) T cells, and the role of CD47 in CAR T-cell function remains largely unknown. Methods Here, we describe the development of CD47-CAR T cells derived from a high affinity signal regulatory protein α variant CV1, which binds CD47. CV1-CAR T cells were generated from human peripheral blood mononuclear cells and evaluated in vitro and in vivo. The role of CD47 in CAR T-cell function was examined by knocking out CD47 in T cells followed by downstream functional analyses. Results While CV1-CAR T cells are specific and exhibit potent activity in vitro they lacked antitumor activity in xenograft models. Mechanistic studies revealed CV1-CAR T cells downregulate CD47 to overcome fratricide, but CD47 loss resulted in their failure to expand and persist in vivo. This effect was not limited to CV1-CAR T cells, since CD47 knockout CAR T cells targeting another solid tumor antigen exhibited the same in vivo fate. Further, CD47 knockout T cells were sensitive to macrophage-mediated phagocytosis. Conclusions These findings highlight that CD47 expression is critical for CAR T-cell survival in vivo and is a ‘sine qua non’ for successful adoptive T-cell therapy.
Society for Immunotherapy of Cancer (SITC) consensus definitions for resistance to combinations of immune checkpoint inhibitors with targeted therapies
Authors: Michael B Atkins, Paolo A Ascierto, David Feltquate, James L Gulley, Douglas B Johnson, Nikhil I Khushalani, Jeffrey Sosman, Timonthy A Yap, Harriet Kluger, Ryan J Sullivan, Hussein Tawbi
Journal: Journal for ImmunoTherapy of Cancer (2023)

Immunotherapy offers deep and durable disease control to some patients, but many tumors do not respond to treatment with single-agent immune checkpoint inhibitors (ICIs). One strategy to enhance responses to immunotherapy is via combinations with signal transduction inhibitors, such as antiangiogenic therapies, which not only directly target cancer cells but also could potentially favorably modulate the tumor immune microenvironment. Combination strategies with ICIs have demonstrated enhanced antitumor activity compared with tumor-targeted or antiangiogenic therapy alone in randomized trials in a variety of solid tumor settings, leading to regulatory approval from the US Food and Drug Administration and agencies in other countries for the treatment of endometrial cancer, kidney cancer, melanoma, and hepatocellular carcinoma. Despite improved survival and response rates for some patients when antiangiogenic or targeted therapies are administered with ICIs, many patients continue to progress after combination treatment and urgently need new strategies to address this manifestation of resistance to immunotherapy. Previously, the Society for Immunotherapy of Cancer (SITC) published consensus definitions for resistance to single-agent anti-PD-(L)1. To provide guidance for clinical trial design and to support analyses of emerging molecular and immune profiling data surrounding mechanisms of resistance to ICI-based combinations, SITC convened a follow-up workshop in 2021 to develop consensus definitions for resistance to multiagent ICI combinations. This manuscript reports the consensus clinical definitions for combinations of anti-PD-(L)1 ICIs and targeted therapies. Definitions for resistance to ICIs in combination with chemotherapy and with other ICIs will be published in companion volumes to this paper.
Preclinical proof of concept for VivoVec, a lentiviral-based platform for in vivo CAR T-cell engineering
Authors: Kathryn R Michels, Alyssa Sheih, Susana A Hernandez, Alissa H Brandes, Don Parrilla, Blythe Irwin, Anai M Perez, Hung-An Ting, Christopher J Nicolai, Timothy Gervascio, Seungjin Shin, Mark D Pankau, Mason Muhonen, Jessica Freeman, Sarah Gould, Rich Getto, Ryan P Larson, Byoung Y Ryu, Andrew M Scharenberg, Alessandra M Sullivan, Shon Green
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background Chimeric antigen receptor (CAR) T-cell therapies have demonstrated transformational outcomes in the treatment of B-cell malignancies, but their widespread use is hindered by technical and logistical challenges associated with ex vivo cell manufacturing. To overcome these challenges, we developed VivoVec, a lentiviral vector-based platform for in vivo engineering of T cells. UB-VV100, a VivoVec clinical candidate for the treatment of B-cell malignancies, displays an anti-CD3 single-chain variable fragment (scFv) on the surface and delivers a genetic payload that encodes a second-generation CD19-targeted CAR along with a rapamycin-activated cytokine receptor (RACR) system designed to overcome the need for lymphodepleting chemotherapy in supporting successful CAR T-cell expansion and persistence. In the presence of exogenous rapamycin, non-transduced immune cells are suppressed, while the RACR system in transduced cells converts rapamycin binding to an interleukin (IL)-2/IL-15 signal to promote proliferation. Methods UB-VV100 was administered to peripheral blood mononuclear cells (PBMCs) from healthy donors and from patients with B-cell malignancy without additional stimulation. Cultures were assessed for CAR T-cell transduction and function. Biodistribution was evaluated in CD34-humanized mice and in canines. In vivo efficacy was evaluated against normal B cells in CD34-humanized mice and against systemic tumor xenografts in PBMC-humanized mice. Results In vitro, administration of UB-VV100 resulted in dose-dependent and anti-CD3 scFv-dependent T-cell activation and CAR T-cell transduction. The resulting CAR T cells exhibited selective expansion in rapamycin and antigen-dependent activity against malignant B-cell targets. In humanized mouse and canine studies, UB-VV100 demonstrated a favorable biodistribution profile, with transduction events limited to the immune compartment after intranodal or intraperitoneal administration. Administration of UB-VV100 to humanized mice engrafted with B-cell tumors resulted in CAR T-cell transduction, expansion, and elimination of systemic malignancy. Conclusions These findings demonstrate that UB-VV100 generates functional CAR T cells in vivo, which could expand patient access to CAR T technology in both hematological and solid tumors without the need for ex vivo cell manufacturing.
All-trans retinoic acid improves NSD2-mediated RARα phase separation and efficacy of anti-CD38 CAR T-cell therapy in multiple myeloma
Authors: Ziyi Peng, Jingya Wang, Jing Guo, Xin Li, Sheng Wang, Ying Xie, Hongmei Jiang, Yixuan Wang, Mengqi Wang, Meilin Hu, Qian Li, Yafei Wang, Jian-Qing Mi, Zhiqiang Liu
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background Immunotherapies targeting CD38 have demonstrated salient efficacy in relapsed/refractory multiple myeloma (MM). However, loss of CD38 antigen and outgrowth of CD38 negative plasma cells have emerged as a major obstacle in clinics. All-trans retinoic acid (ATRA) has been reported to upregulate CD38 expression, but the mechanism and adaptive genetic background remain unexplored. Methods The efficacy of ATRA in upregulating CD38 expression in MM cells is evaluated by flow cytometry. The interaction between NSD2 and the RARα is analyzed by immunoprecipitation, and the nuclear condensation of RARα is evaluated under laser confocal microscope. A graft model of MM is established in NOD. Cg-Prkdc scid Il2rg tm1Wjl /SzJ mice, and the tumor burden is assessed by in vivo fluorescence imaging. Results We report that ATRA upregulates MM cells CD38 in a non-linear manner, which is t(4;14) translocation dependent, and t(4;14) translocation-induced NSD2 shows positive correlation with ATRA-induced level of, but not with basal level of CD38 expression. Mechanistically, NSD2 interacts with the ATRA receptor, RARα, and protects it from degradation. Meanwhile, NSD2 enhances the nuclear condensation of RARα and modifies the histone H3 dimethylation at lysine 36 on CD38 promoter. Knockdown of NSD2 attenuates the sensitization of MM against ATRA induced CD38 upregulation. Translationally, ATRA is prone to augment the efficacy of anti-CD38 CAR T cells in NSD2 high MM cells in vitro and in vivo. Conclusion This study elucidates a mechanism of ATRA in regulating CD38 expression and expands the clinical potential of ATRA in improving immunotherapies against CD38 in patients with MM.Cite Now
Profiling specific cell populations within the inflammatory tumor microenvironment by oscillating-gradient diffusion-weighted MRI
Authors: Emily Hoffmann, Mirjam Gerwing, Stephan Niland, Rolf Niehoff, Max Masthoff, Christiane Geyer, Lydia Wachsmuth, Enrica Wilken, Carsten Höltke, Walter L Heindel, Verena Hoerr, Regina Schinner, Philipp Berger, Thomas Vogl, Johannes A Eble, Bastian Maus, Anne Helfen, Moritz Wildgruber, Cornelius Faber
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background The inflammatory tumor microenvironment (TME) is formed by various immune cells, being closely associated with tumorigenesis. Especially, the interaction between tumor-infiltrating T-cells and macrophages has a crucial impact on tumor progression and metastatic spread. The purpose of this study was to investigate whether oscillating-gradient diffusion-weighted MRI (OGSE-DWI) enables a cell size-based discrimination between different cell populations of the TME. Methods Sine-shaped OGSE-DWI was combined with the Imaging Microstructural Parameters Using Limited Spectrally Edited Diffusion (IMPULSED) approach to measure microscale diffusion distances, here relating to cell sizes. The accuracy of IMPULSED-derived cell radii was evaluated using in vitro spheroid models, consisting of either pure cancer cells, macrophages, or T-cells. Subsequently, in vivo experiments aimed to assess changes within the TME and its specific immune cell composition in syngeneic murine breast cancer models with divergent degrees of malignancy (4T1, 67NR) during tumor progression, clodronate liposome-mediated depletion of macrophages, and immune checkpoint inhibitor (ICI) treatment. Ex vivo analysis of IMPULSED-derived cell radii was conducted by immunohistochemical wheat germ agglutinin staining of cell membranes, while intratumoral immune cell composition was analyzed by CD3 and F4/80 co-staining. Results OGSE-DWI detected mean cell radii of 8.8±1.3 µm for 4T1, 8.2±1.4 µm for 67NR, 13.0±1.7 for macrophage, and 3.8±1.8 µm for T-cell spheroids. While T-cell infiltration during progression of 4T1 tumors was observed by decreasing mean cell radii from 9.7±1.0 to 5.0±1.5 µm, increasing amount of intratumoral macrophages during progression of 67NR tumors resulted in increasing mean cell radii from 8.9±1.2 to 12.5±1.1 µm. After macrophage depletion, mean cell radii decreased from 6.3±1.7 to 4.4±0.5 µm. T-cell infiltration after ICI treatment was captured by decreasing mean cell radii in both tumor models, with more pronounced effects in the 67NR tumor model. Conclusions OGSE-DWI provides a versatile tool for non-invasive profiling of the inflammatory TME by assessing the dominating cell type T-cells or macrophages.
Abstract P505: Midlife Cognitive Function is Associated With Gut Microbial Species and Metabolic Pathways: Coronary Artery Risk Development in Young Adults (CARDIA) Study
Authors: Katie A Meyer, Anju Lulla, Michael Wu, Ryan Demmer, Kristine Yaffe, KRISTINE YAFFE, Kristine Yaffe, Osorio Meirelles, Lenore Launer
Journal: Circulation (2023)

Background: The gut microbiota may play a role in cognitive function and decline. Animal models support mechanisms involving short-chain fatty acid production, amino acid metabolism, and purine metabolism. There is need to replicate these findings in population-based human studies. Methods: Data were from 570 participants who attended the Yr. 30 follow-up exam (2015-16, ages 48-60 y, 45%:55% Black:White race, 45%:55% M:F sex), provided a fecal sample, and completed a cognitive battery of 6 assessments: Montreal Cognitive Assessment (MoCA), Digit Symbol Substitution Test (DSST), Rey-Auditory Verbal Learning Test (RAVLT), Stroop, and Letter and Category Fluency. A global cognition score was derived from the 6 assessments using principal components analysis. Species and metabolic pathways were assigned to whole-metagenomics sequence data using standard reference databases. Multivariable-adjusted linear regression was used to test associations between distinct microbial features and measures of cognition, controlling for false discovery rate (FDR). Results: Sequence data mapped to 106 species and 312 metabolic pathways. In multivariable-adjusted regression analysis, adjusted for socio-demographics, health behaviors, and BMI, 5 species and 5 metabolic pathways were significantly associated with measures of cognitive function, FDR &lt; 0.20 (Figure) . These species/pathways are involved in purine and pyrimidine metabolism and short-chain fatty acid production. Conclusion: Identified pathways play a role in neurodevelopment and in the gut-brain axis of physiologic communications. Our findings suggest long-term relationships between gut microbiota composition and cognitive function.
Abstract P414: Modification of Diet-Metabolite Associations by Race and Sex in the Coronary Artery Risk Development in Young Adults Study
Authors: Autumn G Hullings, Annie Green Howard, Katie A Meyer, Christy L Avery, Kari E North, Sachin Mhatre, Wei Sha, Xiuxia Du, Yuanyan Li, Blake Rushing, Susan Sumner, Cora E Lewis, Penny Gordon-Larsen
Journal: Circulation (2023)

Objective: There is known heterogeneity in the relationship between diet quality and cardiovascular disease by self-reported race and sex, which may underlie inequities in cardiovascular health. Methods: We used data from 2,832 participants in the Coronary Artery Risk Development in Young Adults (CARDIA) study (2005-06, aged 37-55, 57% women, 45% Black). Using fasted blood samples, we obtained ultra-high-performance liquid chromatography high resolution mass spectrometry untargeted metabolomics and derived an a priori diet quality score using a validated diet history questionnaire, based on classification of 46 food groups with potential beneficial (n=20), adverse (n=13), or neutral (n=13) implications for cardiovascular health. We tested effect modification of associations between metabolites and diet quality by race and sex, separately, using multivariable-adjusted linear regression for 7,522 metabolite peaks, accounting for multiple comparisons, adjusted for batch, field center, demographics, lifestyle behaviors, total energy intake, hypertension and diabetes status, medication use, and BMI. We also used race- and sex-stratified multivariate Orthogonal Projections to Latent Structures Discriminant Analysis (OPLS-DA) analyses to examine how metabolites distinguish by diet quality 1 st and 4 th quartiles. We identified differing metabolite pathways by race and sex through biochemical pathway analysis (Mummichog version 1.0.10) from regression and OPLS-DA models. Results: In linear regression, race significantly modified metabolite-diet quality associations for 231 metabolite peaks; sex modified associations for 1 peak (FDR&lt;0.1). OPLS-DA pathway analysis identified cysteine, methionine, histidine, and alpha-linoleic metabolism and terpenoid backbone biosynthesis as significantly associated with diet quality in Black, but not White, race. Linear regression and OPLS-DA pathway analysis found differences (p&lt;0.05) in arginine biosynthesis by sex. OPLS-DA also found aminoacyl-tRNA and arginine biosynthesis, nitrogen, porphyrin, and chlorophyll metabolism were significantly associated with diet quality in men only. Conclusions: Metabolite pathways were statistically different by self-reported race, and to a lesser extent, by sex. Differences in metabolite-diet quality associations may reflect differences in contextual or social variables, and potentially, heterogeneity in metabolism.